We hypothesize that a recombinant yellow fever vaccine (rYF-17D) prime followed by a recombinant virus boost can control viral replication of the AIDS virus. We plan to test this hypothesis in macaques using a rigorous heterologous challenge with a pathogenic SIV swarm, SIVsmE660. YF-17D is an outstanding candidate vector for delivering HIV antigens. It is one of the most successful human vaccines ever made. Vaccination with a single dose of the live attenuated YF-17D virus causes a selflimited viral infection and promotes the generation of neutralizing antibodies and T cell responses that provide protective long-lasting immunity in more than 95% of vaccinees. Vaccine manufacturing is well established, and more than 400 million humans have been vaccinated with minimal incidents of severe side effects. YF-17D vaccination leads to a polyvalent adaptive immune response, which includes the induction of CD8+ T cells and a mixed T helper 1 (TH1) and TH2 cell profile. Immunization also promotes CD8+ T cell migration to mucosal surfaces. Our collaborators have also generated new data showing that rYF-17D can serve as an outstanding prime for a viral vector boost. They have also constructed and stabilized two novel rYF-17D vectors. We have previously shown that a rDNA prime followed by a rAd5 boost can control replication of the heterologous E660 challenge. Unfortunately, the safety of Ad5 as a vector has been questioned by the recent STEP trial. Since Ad26 has many of the good immunogenic qualities of Ad5, we will therefore use rAd26 instead of rAd5 in our first series of experiments. We will vaccinate macaques using Gag, Vif and Env. We will also determine whether rYF-17D vector can prime for a recombinant vesicular stomatitis virus (rVSV) boost. These experiments will allow us to determine whether rYF-17D has the potential to be advanced into human clinical trials as a prime for a recombinant viral boost.